Prostate cancer is a clinically heterogeneous disease with marked variability in outcomes. It is the second most common cancer in men worldwide and causes over 250,000 deaths each year (JEMAL (2011)). Yet, overtreatment of indolent disease also results in significant morbidity (DASKIVICH 2011). A deeper understanding of the molecular pathogenesis of prostate cancer is needed to guide the deployment of new therapies and to distinguish benign from aggressive disease. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) (HE (1997), BHATIA-GAUR (1999)) and PTEN (10q23) (LI (1997), CAIRNS (1997)), gains of the androgen receptor gene (AR) (LINJA (2004), VISAKORPI (1995)) and fusion of ETS-family transcription factor genes with androgen-responsive promoters (PERNER (2006), TOMLINS (2007), TOMLINS (2005)). These discoveries raise the possibility that prostate cancer might soon transition from a poorly understood, clinically heterogeneous disease to a collection of homogenous subtypes identifiable by molecular criteria.
In contrast to the well-defined genomic lesions in prostate cancer, protein-altering point mutations are uncommon. The overall and protein-altering mutation rate of primary prostate cancer is among the lowest reported, approximately an order of magnitude lower than other cancers (BERGER (2011), KAN (2010)). Consistent with this, recurrent protein-altering mutations are rare in prostate cancer. Mutations in AR, PTEN, and AKT1 are among the most common (FORBES (2011), BOORMANS (2010)); these occur rarely in primary prostate cancer, with reported frequency around 1% (TAYLOR (2010)). Accordingly, this study examined the point mutations present in a large cohort of prostate cancer patients and discovered recurrent mutations in the substrate binding cleft of SPOP in the cohort were associated with a distinct molecular subtype of prostate cancer.